Is ASPM p.Leu2451= (c.7353G>A) pathogenic?

ASPM p.Leu2451= (c.7353G>A) is classified Benign/Likely benign in ASPM (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). Low-frequency (popmax 2.92%, afr); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Leu2451= (c.7353G>A)?

ASPM p.Leu2451= (c.7353G>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Leu2451= (c.7353G>A) in the general population?

ASPM p.Leu2451= (c.7353G>A) is low-frequency (popmax 2.92%, afr) (gnomAD).

ASPM p.Leu2451=

c.7353G>A · rs111487086 · VCV157868

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.92%, afr)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -0.92
Overall
CADD	0.444	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.92% African / African-American · 2,183/74,870 alleles

Filtering AF 2.81% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.77%

Overall 0.222% 3,584/1,612,794 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.92%	34
Ashkenazi Jewishnot grpmax-eligible	1.58%	63
Middle Eastern	0.743%	135
Remaining individualsnot grpmax-eligible	0.445%	225
Admixed American	0.232%	430
European (non-Finnish)	0.0376%	2,656
South Asian	0.0307%	3,252

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ASPM
Protein: p.Leu2451=
Coding: c.7353G>A
MANE Select: NM_018136
dbSNP: rs111487086
Type: single nucleotide variant
Location: chr1:197101898 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full ASPM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 5, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPM c.2419+2T>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.2488-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.2936+5G>A Likely pathogenic ★★ same condition
ASPM c.3082+1G>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.9084+5G>A Likely pathogenic ★★ same condition
ASPM p.Arg1019Ter Pathogenic ★★ same condition
ASPM p.Arg1271Ter Pathogenic ★★ same condition
ASPM p.Arg1538Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aspm-p-leu2451 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown